Mice studies show how lack of shut-eye impairs memory
WASHINGTON — Losing sleep damages the brain’s ability to make memory-building proteins, new research in mice suggests.
Raising protein production in one of the brain’s learning and memory centers erased the forgetfulness that comes with sleep deprivation, neuroscientist Jennifer Tudor of the University of Pennsylvania reported November 17 at the annual meeting of the Society for Neuroscience.
Tudor and her colleagues have been trying to identify the molecular fingerprint that sleep deprivation leaves on the hippocampus, a seahorse-shaped brain structure involved in forming and solidifying memories. Previously, the researchers discovered that keeping mice up late altered the activity of more than 500 genes. Among those genes were some involved in the protein-building process known as translation.
Overall protein production dropped in sleep-deprived mice compared with well-rested ones. Among the plummeting proteins were some involved in a communication network inside cells known as the mTOR pathway. That pathway governs various processes, including cell growth, survival, movement, gene activity, protein production and a type of self-recycling process called autophagy. Disruption of the system can lead to cancer and other diseases.
Tudor and colleagues boosted levels of an mTOR pathway protein known as 4E binding protein 2, or 4EBP2, in the hippocampi of some mice. Normally, 4EBP2 latches on to a molecule needed for translation and shuts down the process. When cells get signals that more protein is needed — as might happen when building a memory — mTOR and a partner protein attach phosphate to 4EBP2, causing it to let go of the molecule, allowing protein production to proceed.
In the experiment, the researchers boosted 4EBP2 above normal levels. Levels of the phosphate-laden form rose as well, although Tudor doesn’t yet know what is causing the phosphorylation. Making more of the phosphorylated form of 4EBP2 allowed hippocampal cells to produce more proteins overall, the researchers found.
To see if fixing the protein-production problem also repaired the memory deficits, the researchers gave mice a memory test. Mice were put in a cage with three objects: a metallic tower, a glass bottle and a plastic syringe. Tudor and colleagues gently handled some mice to keep them up for five hours past their normal bedtime. Others got a full night’s sleep.
The next day, the researchers returned the mice to the cage with the three objects, but this time, one of the items was in a different location. Well-rested rodents spent more time sniffing and exploring the displaced object than the undisturbed ones. Sleep-deprived mice spent roughly equal amounts of time playing with each item, indicating that they didn’t remember the previous location and couldn’t tell that one had been moved. Sleep-deprived mice that made more 4EBP2 in their hippocampi remembered the objects and reacted to the displaced one similarly to well-rested mice.
Offsetting a drawback of sleep deprivation is an interesting idea, said Jonathan Lipton, a chronobiologist and sleep neurologist at Boston Children’s Hospital and Harvard Medical School. But such broad-scale tinkering with the mTOR system is probably not a feasible approach because of many possible negative side effects. The next step will be for the researchers to determine which specific proteins must be made to enable memory formation, he said.
J.H. Choi et al. Restoration of phosphorylated eukaryotic translation initiation factor 4E binding protein 2 (4EBP2) in the hippocampus rescues memory impairment due to sleep deprivation. Society for Neuroscience Meeting, Washington, D.C., November 17, 2014.
C.G. Vecsey et al. Genomic analysis of sleep deprivation reveals translational regulation in the hippocampus. Physiological Genomics. Vol. 44, October 15, 2012, p. 981. doi: 10.1152/physiolgenomics.00084.2012.